{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T12:05:06Z","timestamp":1779365106835,"version":"3.53.0"},"reference-count":55,"publisher":"Portland Press Ltd.","issue":"6","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C18281\/A29019"],"award-info":[{"award-number":["C18281\/A29019"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Obesity contributes to colorectal cancer (CRC) by elevating levels of estrogen, 27-hydroxycholesterol (27-OHC), and insulin-like growth factors. Paradoxically, epidemiological studies show that hormone replacement therapy reduces CRC incidence and mortality, particularly in postmenopausal women, suggesting a protective role for estrogen. Estrogen and 27-OHC signal via ER\u03b1, ER\u03b2, and G protein-coupled estrogen receptor 1 (GPER1), with ER\u03b2 being the predominant estrogen receptor in the colon. We observed a strong positive correlation between ER\u03b2 and insulin-like growth factor-binding protein-5 (IGFBP-5) in CRC tissues, and high IGFBP-5 expression was significantly associated with poor patient outcomes. Functional assays revealed that ER\u03b2 knockdown inhibited colon cancer cell proliferation and migration, accompanied by a marked reduction in IGFBP-5 expression. Co-immunoprecipitation confirmed a direct interaction between ER\u03b2 and IGFBP-5. Both estrogen and 27-OHC suppressed CRC cell proliferation and IGFBP-5 expression, but this was independent of ER\u03b2. Combined ER\u03b2 silencing and estrogen or 27-OHC treatment enhanced DNA damage and apoptosis. Transcriptome analysis identified GPER1 as a downstream estrogen-responsive gene. Subsequent in vitro validation confirmed that GPER1 activation mediates the tumour-suppressive effects of estrogen and 27-OHC. Collectively, our findings highlight IGFBP-5 as a potential prognostic marker, demonstrate the tumour-inhibitory effect of ER\u03b2 silencing, and identify GPER1 as a promising therapeutic target linking estrogen signalling, lipid metabolism, and CRC progression.<\/jats:p>","DOI":"10.1042\/cs20258451","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:49:44Z","timestamp":1777373384000},"page":"1011-1032","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unravelling the effects of selective estrogen receptor modulators on colorectal cancer: a prognostic role for insulin-like growth factor binding protein-5"],"prefix":"10.1042","volume":"140","author":[{"given":"Xiaoyu","family":"Su","sequence":"first","affiliation":[{"name":"1Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel\u00a0M.","family":"Barker","sequence":"additional","affiliation":[{"name":"1Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"McCarthy","sequence":"additional","affiliation":[{"name":"1Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, U.K."},{"name":"2North Bristol NHS Trust, Southmead Hospital, Southmead Road, Bristol BS10 5NB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalina","family":"Biernacka","sequence":"additional","affiliation":[{"name":"1Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astor","family":"Mak","sequence":"additional","affiliation":[{"name":"1Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1562-891X","authenticated-orcid":false,"given":"Claire\u00a0M.","family":"Perks","sequence":"additional","affiliation":[{"name":"1Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"2026052107062768500_B1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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